TERT-dependent senescence and inflammation in ageing, using zebrafish as a model

Uncovering the mechanisms underlying ageing of the central nervous system (CNS) is crucial to identify therapeutic targets to promote healthy ageing. Although the CNS is considered predominantly post-mitotic, it has been suggested that telomerase, mostly known for its role in cell division through maintenance of telomere length, has a protective role against cellular senescence. However, the mechanisms underlying this remain unclear. Here, I aimed to determine telomerase-dependent mechanisms of ageing in the CNS, particularly in the retina and the brain. To do so, I used wild-type zebrafish alongside with the telomerase-mutant (tert-/-) zebrafish model. This study shows that zebrafish display retina degeneration and visual impairment with ageing, and that these occur in a telomerase independent manner. Despite preserving its regenerative capacity in response to acute damage until old ages, rather than regeneration, the aged zebrafish retina undergoes gliosis, like in humans. This highlights zebrafish as a suitable model to explore relevant mechanisms to neurodegeneration in the human retina, during ageing, pointing to gliosis as a key target to explore endogenous regeneration mechanisms. When looking at the brain, this study shows an accumulation of senescence markers, specifically in the diencephalon and cerebellum. Contrasting with the retina, in the brain, these hallmarks were accelerated in the tert-/- model, suggesting that TERT exerts a protective role against accumulation of senescence in the aged brain. Here, I also identify a set of genes potentially involved in TERT-dependent senescence in the ageing brain, but further investigation is required to test whether the expression of these genes delay accumulation of senescence in the aged zebrafish brain. Together, this opens new lines of investigation on telomerase-dependent and independent mechanisms of ageing, pointing to zebrafish as a valuable model to further explore potential therapeutic targets aiming to ameliorate retina and brain degeneration with ageing.